Sex hormones and HCV-related liver disease progression

性激素和 HCV 相关肝病进展

基本信息

批准号：
9979785
负责人：
Donna Lorraine White
金额：
--
依托单位：
MICHAEL E DEBAKEY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979785
关键词：
Accounting Aging Alcohol consumption Alcoholic Fatty Liver Androgen Antagonists Androgens Animal Model Bioavailable Biological Biological Markers Blood specimen Carrier Proteins Chronic Hepatitis C Cirrhosis Clinical Cohort Studies Computerized Medical Record Consensus Cross-Sectional Studies DNA Data Databases Diagnosis Disease Progression Drug Prescriptions Electronic Health Record Estradiol Etiology Female Fibrosis Finasteride Gender General Population Genes Geographic Locations Gonadal Steroid Hormones Healthcare Hepatitis C Hepatitis C virus Hormone use Individual Laboratories Liver Liver Failure Liver diseases Long-Term Effects Malignant neoplasm of liver Measures Medical center Medicine Molecular Epidemiology Outcome Patients Performance Pharmaceutical Preparations Pharmacoepidemiology Physicians Play Population Prevalence Primary Health Care Primary carcinoma of the liver cells Probability Prognosis Race Regimen Research Retrospective cohort study Risk Risk Factors Role Same-sex Sample Size Sampling Sex Hormone-Binding Globulin Stanolone Surveys Testing Testosterone Time Variant Veterans Viremia age group anti-hepatitis C chronic infection clinical practice clinical risk cohort cost design dimorphism disorder risk electronic data epidemiology study genetic variant improved infection rate lifetime risk liver transplantation male member men non-alcoholic fatty liver disease novel novel therapeutics phenotypic data prospective recruit research study response risk stratification routine care searchable database sex risk sexual dimorphism therapeutic target virology

项目摘要

Over 260,000 male veterans accessing VA healthcare between 2000 and 2014 had a laboratory confirmed diagnosis of hepatitis C virus (HCV) infection. Chronic HCV infection (HCV+) is the leading cause of liver disease progression to cirrhosis, liver transplant and liver cancer. HCV+ males have much higher rates of liver disease progression than HCV+ females. One factor that may contribute to this difference is large and gender- defining biological differences in the levels of circulating sex hormones like testosterone. However, the role normal variability in these major sex hormones plays in risk of liver disease progression among HCV+ individuals of the same gender is not known. The long-term effects of medications that substantially alter sex hormone levels like testosterone therapy on risk of disease progression in HCV+ males are also unknown. We previously recruited baseline cohort of 1072 male veterans with chronic HCV infection seen for routine care at single VA. All completed a lifetime risk factor survey and had a blood sample taken to obtain DNA and to store for biomarker testing in approved future research studies. We propose to measure circulating levels of major sex hormones at baseline using stored blood samples for this cohort of 1,072 HCV+ male veterans. We will also perform DNA tests to assess specific variations in several genes related to sex hormone function. We will prospectively follow all cohort members for liver disease progression with outcomes determined using electronic medical record review and VA database searches and expert physician consensus review. We will examine the association between baseline levels of sex hormones after accounting for sex hormone gene variants on risk of liver disease progression including to cirrhosis and liver cancer in our baseline HCV+ male cohort from 1-9 years later. We propose to measure use of commonly prescribed medications that alter levels of androgen sex hormones like testosterone in the >267,000 males with laboratory confirmed HCV and seen at the VA between 2000 and 2014. We will extract extensive information about each individual at baseline to account for their likelihood to ever receive these medications and calculate medication propensity scores. We will account for these propensity scores in our assessment of the association between use of these hormone altering medications and risk of HCV-related liver disease progression from 1-18 years later. In addition to uncovering new potential therapeutic targets for HCV-related liver disease progression, this study has rapid and important potential impact on clinical practice in terms of better criteria to risk stratify veterans and help prioritize them for early access to costly new anti-HCV medications and may alter practice for prescribing sex hormone altering medications in aging HCV-infected males.

在2000年至2014年之间，超过260,000名男性退伍军人获得了VA医疗保健丙型肝炎病毒（HCV）感染的诊断。慢性HCV感染（HCV+）是肝的主要原因疾病发展为肝硬化，肝移植和肝癌。 HCV+男性的肝脏发生率要高得多疾病进展比HCV+女性。可能导致这种差异的一个因素很大，性别 - 定义生物学差异在循环性激素等水平（如睾丸激素）水平上。但是，角色这些主要性激素的正常变异性在HCV+中具有肝病进展的风险同一性别的个人尚不清楚。实质性改变性的药物的长期影响 HCV+男性疾病进展风险等激素水平也未知。我们以前招募了1072名男性退伍军人的基线队列，患有慢性HCV感染，可用于常规护理在单个VA。全部完成了终身危险因素调查，并取了一个血液样本以获得DNA和在未来的研究研究中存储生物标志物测试。我们建议测量循环基线时使用储存的血液样本的主要性激素水平为1,072 HCV+男性退伍军人。我们还将执行DNA测试以评估与几个基因相关的特定变异到性激素功能。我们将前瞻性地跟随所有队列成员进行肝病的进展使用电子病历审查和VA数据库搜索和专家医师确定的结果共识评论。我们将检查性激素基线水平之间的关联考虑性激素基因变异的肝病进展风险，包括从1 - 9年后，我们的基线HCV+雄性队列中的肝硬化和肝癌。我们建议测量使用常规药物改变雄激素水平的使用在> 267,000名男性中，具有实验室的性激素，例如睾丸激素，确认了HCV并看到在2000年至2014年之间的VA上。我们将提取有关每个人的广泛信息基线以考虑他们曾经接受这些药物并计算药物倾向的可能性分数。我们将在评估协会的评估中考虑这些倾向分数在使用这些激素改变药物和与HCV相关肝病的风险之间 1 - 18年后的进展。除了发现与HCV相关肝脏疾病进展的新的潜在治疗靶点外，根据更好的标准，研究对临床实践产生了快速而重要的潜在影响。退伍军人并帮助他们优先考虑及早获得昂贵的新抗HCV药物，并可能会改变实践用于开出衰老的HCV感染男性的性激素改变药物。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Post-Traumatic Stress Disorder is Associated with further Increased Parkinson's Disease Risk in Veterans with Traumatic Brain Injury.

创伤后应激障碍与脑外伤退伍军人帕金森病风险进一步增加有关。

DOI：
10.1002/ana.25726
发表时间：
2020
期刊：
Annals of neurology
影响因子：
11.2
作者：
White,DonnaL;Kunik,MarkE;Yu,Hong;Lin,HelenL;Richardson,PeterA;Moore,Suzanne;Sarwar,AliyaI;Marsh,Laura;Jorge,RicardoE
通讯作者：
Jorge,RicardoE